In Orientals, ALDH2 deficiency due to the common polymorphism Glu487Lys frequently causes a flushing reaction after alcohol consumption and this aversive reaction is responsible for lower rates of alcoholism in individuals with the inactive Lys487 allele. R. Peterson identified a series of additional markers at ALDH2. By restriction enzyme analysis, SSCP, and sequencing, haplotypes characteristic for the two ALDH2 alleles were identified. This analysis has shed light on the origins and functional role of the Lys487 allele, which appears to have originated once, on a single haplotype lineage, and spread among East Asian populations. Furthermore, although it probably originated on a single genetic background, haplotype analysis reveals that the mutation was sufficiently ancient for additional mutations to have occurred subsequently. The results on ALDH2 haplotypes are most compatible with an effect of selection to maintain the Oriental ALDH2 variant, Glu487Lys. We are investigating the relationship of ADH and ALDH functional alleles to alcoholism and other substance abuse phenotypes. These genotype/phenotype relationships are being studied in combination with other loci, for example the OPRM1 receptor locus in opioid addiction.